The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Detrusor urethral sphincter dyssynergia (DUSD) and its current therapies
Normal voiding consists of sustained relaxation of periurethral smooth and striated muscle during sustained detrusor contraction. The anatomy of the lower urinary tract in human (a) and in rat (b) is shown in FIG. 2. In this Figure D denote detrusor, U urethra, RB rhabdosphincter (striated urethral sphincter), PR prostate, VPR ventral prostate, LPR lateral prostate, S seminal vesicle, C coagulating gland and UR urogenital diaphragm. Inappropriate contraction or failure of complete and sustained relaxation of the urethral musculature during detrusor contraction causes voiding problems known as detrusor urethral sphincter dyssynergia. The etiopathogenesis of detrusor urethral sphincter dyssynergia is poorly understood. Three different clinical outcomes have been described: 1) bladder neck dyssynergia, 2) external sphincter pseudodyssynergia and 3) Hinman syndrome. They all are defined in this invention as detrusor urethral sphincter dyssynergia.
In the following we summarize the clinical symptoms of male functional detrusor urethral sphincter dyssynergia and its treatments taking into account especially the possible hormonal background of the symptoms.
According to the recent study (Kaplan et al. 1996) half of the men younger than 50 years old with chronic irritative and/or obstructive voiding symptoms have primary bladder outlet obstruction (bladder neck dyssynergia), and in every fourth patient, the obstruction is located to the membraneous urethra (termed as pseudodyssynergia of the external sphincter).
Bladder neck dyssynergia
The bladder neck dyssynergia patient is a male aged between 20 and 60 years. Bladder neck dyssynergia is usually a life-long condition. It virtually never occurs in females. At old ages, prostatic enlargement and bladder neck dyssynergia are both common conditions so their coincidence is by no means uncommon.
Symptoms of bladder neck dyssynergia are hesitance, poor urinary stream, terminal drippling and incomplete bladder emptying (Prostatic Obstruction. Pathogenesis and treatment. Ed. Christopher R. Chapple. Springer-Verlag 1994). In bladder neck dyssynergia an increased intraluminal bladder pressure in needed to empty the bladder. In the initial stages, there is no reduction in the flow rate because the maximum micturition pressure compensates for the increased outflow resistance. Patients with bladder neck dyssynergia may develop secondary detrusor instability with irritative symptoms of frequency, urgency and nocturia.
In bladder neck dyssynergia, the proximal urethra actively tightens during voiding. Smooth muscle fibers of the proximal part of the male bladder neck are morphological extensions of the cholinergically innervated detrusor fibers. The smooth muscle fibres of the distal part of the male bladder neck are morphologically distinct from the detrusor fibres and have .alpha.-adrenergic innervation. It is possible that dysfunctional bladder neck has abnormal composition or arrangements of the smooth muscle fibers. Alterations in the contractile properties or responses of smooth muscle cannot be excluded, either. There is little evidence to support the role of smooth muscle cell hyperplasia or hypertrophy in the development of the dysfunction in men.
Bladder neck dyssynergia can be treated surgically by transecting the full thickness of the bladder neck musculature. The selective .alpha.1-adrenoceptor antagonists, such as prazosin and indoramin inhibit symphatetic tone which is supposed to exacerbate the degree of obstruction of urethra through contraction of urethral smooth muscle. They used as an adjunct in the symptomatic treatment of functional urethral obstruction. Uroselective .alpha.1-antagonists with high tissue selectivity for lower urinary tract smooth muscle that do not provoke hypotensive side-effects are under development.
External sphincter pseudodyssynergia
Increased voiding pressure or decreased flow rate are not necessarily only associated with structural or functional changes in the smooth muscle component of the lower urinary tract. Distally the prostatic urethra possesses a smooth muscle merging with the prostatic musculature. Caudal to the prostate, the urethral wall has a striated muscle layer called rhabdosphincter, urethral sphincter or external sphincter. The striated muscle extends throughout the length of the pre-penile urethra (Oelrich 1980). The proximal portion of the sphincter lies as a bundle between the base of the bladder and the proximal border of the prostate. The fibers in the central portion of the sphincter cover the lateral surface of the prostate. Caudal to the prostate, striated muscle form a horse-shoe -shaped configuration (Strasse et al. 1996). Inferior to the pelvic diaphragm, the sphincter (external sphincter) expands to fill the area between the pudendal canals (Oelrich 1980). There is no subdivision of the human urethra sphincter muscle, and no smooth muscle septa have been recognized dividing the muscle.
During the normal micturition cycle, an increase in external sphincter electromyographic activity accompanies bladder filling (continence reflex). This is followed by relaxation of the urethral sphincter and the pelvic floor muscles, which begins before or at the beginning of the detrusor contration and persists throughout the contration. External sphincter dyssynergia is defined as an inappropriate increase in striated urethral muscle (external urethral sphincter) activity during a detrusor contraction and is a well recognized cause of voiding dysfunction in patients with upper neurone lesions. This overcompensation is done to counteract the elevated bladder pressure caused by uninhibited detrusor contraction (an exaggerated continence reflex) (Rudy et al. 1988).
Most striking in all of the patients with pseudodyssynergia is the presence of contraction of the striated urethral/external sphincter during voiding (Kaplan et al. 1997). In adults, the etiology of the sphincter pseudodyssynergia may be less neurological and more functional which can be seen as narrowing of or cutting off the urinary stream during micturition (Kaplan et al. 1997). Men who have pelvic floor spasm or what Kaplan et al. (1996) term as pseudodyssynergia, may not have severely elevated voiding pressures. However, they have narrowing of the urinary stream during voiding at the level of the membraneous urethra.
Hinman syndrome
Urodynamic investigations in children with an abnormal voiding pattern have shown dyssynergia between the detrusor and striated urethral sphincter in the absence of neurologic disease (nonneurogenic neurogenic bladder or the Hinman syndrome) (Hinman and Baumann, 1973). This appears to result from unintentional, habitual contractions of the striated urethral sphincter in response to involuntary bladder contraction to prevent urinary incontinence. This dyssynergia probably may at least partly represent a learned habit. Its more common among girls than boys. Pharmacologic manipulation of detrusor and sphincter function and biofeedback therapy have been highly successful. The relationship between the Hinman syndrome and the detrusor sphincter dyssynergia or urethral sphincter pseudodyssynergia is not known.
We suggest that the development of detrusor urethral sphincter dyssynergia is associated to estrogen or androgen/estrogen ratio. To the best of our knowledge, the hormonal etiology for the male detrusor urethral sphincter dyssynergia has not been considered earlier.
Decreased androgen to estrogen ratio (DATER)
Elderly women are known to experience commonly postmenopausal syndromes during and after the menopause. In men the hormonal changes are not as dramatic as in women, but recently more attention has been paid to andropause. There are at least three groups of men who are exposed to excessive amounts of estrogens and have relative androgen deficiency. One group includes sons of mothers who have been given diethylstilbesterol (DES) to prevent threatening abortion and gynecomastic boys whose fat tissue is an extra source of estrogens and who may be exposed to estrogen throughout their life, or overweighed elderly men whose low physical activity allows accumulation of fat tissue producing high amounts of estrogens. Another group consists of elderly men who have been exposed to environmental estrogens and men on high fat and low fibre diets. A relative androgen deficiency is a common phenomenon in obese elderly men. The prevalence of androgen deficiency is about 20% in men aged 60 to 80 yrs and 35% in men over 80 yrs. In contrast to severe symptoms in women, the andropause develops slowly and easily remains unrecognized.
In theory, DATER can be treated by testosterone. However, testosterone is converted in the body by aromatase enzyme to estrogens. The long term effect may actually be decreased production of endogenous androgens and concomitantly increased androgen to estrogen ratio. Therefore high doses of testosterone may cause hypogonadism and endocrinological effects which resemble estrogenization. There is no clinically established medicine for the treatment of DATER.
Possible role of estrogens in the development of detrusor urethral sphincter dyssynergia; Estrogen receptors and actions in the lower urinary tract of the experimental animals and men
Although there is no direct evidence to support the role of estrogens in the development of the detrusor urethral sphincter dyssynergia in man there are data to support this: 1. estrogens increase both the density of adrenergic receptors and the adrenergically mediated contractile responses of urethral smooth muscle; and 2. estrogens alter, by preventing androgen-induced sex differentiation or by maintaining of estrogen-dependent structures, the innervation of striated urethral sphincter and the pelvic floor muscles; both of these two estrogen actions could alter the function of the lower urinary tract, and account for the detrusor urethral sphincter dyssynergia.
As a sign of estrogen responsiveness, human bladder and urethra have shown to contain stromal estrogen receptors (ER). The concentrations of estrogen receptors in the trigonum and bladder are considerably lower than those in the urethra (Iosif et al. 1981). Further, the concentrations are higher in the middle and distal thirds of the female intrapelvic urethra in comparison to proximal urethra (Wilson et al. 1984). This suggests that the middle and distal urethra are the most estrogen-sensitive parts in the female lower urinary tract. The female pelvic floor muscles and ligaments also possess estrogen receptors (Smith et al. 1990).
It is known that estrogen can influence the response of urethra to alfa adrenergic stimulation. .alpha.-adrenoceptors play a significant role in the maintenance of intraurethral pressure. In the sexually mature male, the .alpha.-adrenoceptors in urethra are mainly of the .alpha.1-subtype. .alpha.1-adrenoceptors are unevenly distributed along the male urethra (Yablonsky et al. 1991). The highest densities of .sup.3 H-prazosin binding sites have been found in the preprostatic urethra of the dog. The binding sites were localized on the smooth muscle fibers. Urethral striated muscle had no .alpha.1-adrenoceptors.
In the female urethra, .alpha.2- adrenoceptors predominate. The sex difference in the densities of .alpha.1- and .alpha.2-receptors between the male and female urethra may be due to estrogen. In the female rabbit urethra, the estrogen-induced increased sensitivity to norephinephrine is attributable to an increase in the number of postjuntional .alpha.2-adrenoceptors (Larsson et al. 1984). Further, castration of the male rabbit increased .alpha.2-receptor density slightly but it was increased markedly after estrogen administration (Morita et al. 1992). .alpha.1-adrenergic receptor densities decreased significantly after castration, and were not affected by estrogen administration. As a conclusion, estrogen may decrease the ratio of .alpha.1- to .alpha.2-receptors in the smooth muscle of the male urethra, and by this change alters the sympathetic control of urethral contraction.
The second possibility for estrogen interference with the control of the male voiding lies in the innervation of urethral striated muscle. There are sexually dimorphic nuclei in the spinal cord. The volumes of the nuclei of the male rat are larger than those of the female. It is known that higher levels of androgens in male rats prevent SNB (the spinal nucleus of the bulbocavernosus) and DLN (the dorsolateral nucleus) motoneurons from dying during early developoment. The levator ani is among the targets of SNB. The DLN has two targets: the ischiocavernosus, and the striated urethral sphincter. Androgens can also prevent synapse elimination in the sexual dimorphic levator ani muscle and alter the pattern of innervation that is seen in adulthood. The hormone-induced loss of neurones and synapses could simulate the well recognized cause of the inapproriate increase in sphincteric activity during a detrusor contraction seen in patients with upper neurone lesions.
Besides growth inhibition, long-term administration of estrogen or aromatizable androgen to intact or castrated adult males of various animal species promotes prostatic growth at distinct periurethral sites. These sites responding to estrogen treatment with induction of epithelial metaplasia, hyperplasia or dysplasia have been found to occur in the prostate of several animal species (monkeys, dogs, guinea pigs, rats and mice). The location of nuclear estrogen receptors (ERs) found in the stroma corresponds to the sites of histological changes demonstrated in the monkey, dog and mouse. ERs have also been found in the periurethral region of the human prostate, suggesting a homology of the posterior periurethral region of the prostate (containing the collecting ducts and periurethral glands) across the species. To our knowledge, none of the models of estrogen-related altered prostatic growth have been characterized urodynamically, and thus the pathophysiological significance of estrogen-related altered periurethral prostatic growth for voiding remains unclear. As signs of possible urethral obstruction, enlarged bladder, thickened bladder wall and bladder stones have occasionally been seen in estrogen-treated animals. Although higher than physiological blood levels of the female hormone are required for promotion of periurethral prostatic growth in adult animals, its occurrence suggests that estrogen or the decreased androgen to estrogen ratio may be involved in the normal and hyperplastic growth of the human prostate as well as in the development of detrusor urethral sphincter dyssynergia.